Compounds of formula II are therapeutically active compounds
wherein    R1 and R1′ are each independently hydrogen, lower alkyl, alkoxy, halogen, cyano or alkylamino;    R2 is —N(R3)2, —N(R3)(CH2)nOH, —N(R3)S(O)2-lower alkyl, —N(R3)S(O)2-phenyl, —N═CH—N(R3)2, —N(R3)C(O)R3 or a cyclic tertiary amine of the formula
each R3 is independently hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;    R4 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO-lower alkyl, —N(R3)CO-lower alkyl, hydroxy-lower alkyl, cyano, —(CH2)nO(CH2)nOH, —CHO or a 5-or 6 membered heterocyclic group that is optionally bonded via an alkylene group.    R5 and R5′ are each independently hydrogen or lower alkyl or together with the carbon atom to which they are attached form a cycloalkyl group;    R6 and R6′ are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano; or    R6 and R6′ together form —CH═CH—CH═CH—, which is optionally substituted by one or two substituents selected from lower alkyl or lower alkoxy;    X is —C(O)N(R3)—, —(CH2)mO—, —(CH2)mN(R3)—, —N(R3)C(O)—, or —N(R3)(CH2)m—;    n is 0-4; and    m is 1 or 2.
Compounds of formula II are described in EP-A-1035115, such as
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-thiomorpholin-4-yl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-(1-oxo-1λ6-4-thiomorpholin-4-yl)-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-(1,1-dioxo-1λ6-6-thiomorpholin-4-yl)-N-methyl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-N-methyl-4-o-tolyl-nicotinamide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-N-methyl-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl-N-methyl-N-(4-o-tolyl-pyridin-3-yl)-isobutyramide,    2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-pyrimidin-2-yl-piperazin-1-yl)-4—o—tolyl-pyridin-3-yl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-dimethylamino-pyridin-3-yl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-piperazin-1-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, and
2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide.
These compounds of formula II are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease. Furthermore, these compounds are useful in the treatment of pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular inflammatory diseases. Furthermore, the compounds may be useful in the treatment of a number of physiological disorders, which include disorders of the central nervous system such as anxiety, depression and psychosis. The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness, for treatment induced vomiting and for the reduction of cisplatin-induced emesis.
The compounds of formula II can be manufactured according to e.g. EP-A-1035115. In one such method of manufacture, compounds of formula II are prepared from compounds of formula I.
Compounds of formula I
wherein    R1 and R1′ are each independently hydrogen, lower alkyl, lower alkoxy, halogen, cyano or alkylamino;    R2 is —N(R3)2, —N(R3)(CH2)nOH, —N(R3)S(O)2-lower alkyl, —N(R3)S(O)2-phenyl,-N═CH—N(R3)2, —N(R3)C(O)R3 or a cyclic tertiary amine of the formula
each R3 is independently from each other, hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;    R4 is hydrogen, hydroxy, lower alkyl, —(CH2)nCOO-lower alkyl, —N(R3)CO-lower alkyl, hydroxy-lower alkyl, cyano, —(CH2)nO(CH2)nOH, —CHO or a 5-or 6-membered heterocyclic group that is optionally bonded via an alkylene groupare valuable intermediate products for the manufacture of therapeutically active compounds of formula II.
It is known (EP-A-1035115) that the present compounds of formula I can be prepared for example, by processes described in scheme 1 below:

This method for manufacturing the compounds of formula I is high-yielding but requires the use of expensive starting materials. Furthermore, the key step in this method is the substitution of the pyridine with R1R1′C6H3MgCl by Grignard Reaction. The success of this reaction depends on the substitution pattern on the aromatic ring. In case that electron withdrawing groups decrease the reactivity of the Grignard reagent, a Suzuki type reaction (Suzuki Coupling) must be performed.
The problem at the root of the present invention is therefore to provide a process for preparing the compounds of formula I, which process is preferred in case the Grignard Reaction will not work or does not work well.